الفهرس 
Chapter I : IntroductionOnly 14 pages are availabe for public view
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Abstract
The present work includes three main parts, Synthesis, biological evaluation and molecular docking of the novel quinazolinone and quinazolinethione derivatives. These parts can be summarized as following: 1.Chemistry part: This part is presented by the following schemes: Scheme 2.5 Synthesis of 3-substituted 6-aryldihydroisoindolo[2,1-a]quinazoline-5,11-diones 127a-j using ultrasound radiation. Compounds 127a-j were afforded through one-pot multicomponent reaction of 5-haloisatoic anhydride with 2-formylbenzoic acid and different amines through cyclization reaction that involves three consecutive steps of condensation reaction and nucleophilic substitution. Acetic acid was the solvent of choice and the reaction proceeded under ultrasound irradiation at 80 oC. Compounds 143a-h were afforded by reaction of substituted isatoicanhydride with different amines. The reaction was performed in two methods. Method A was performed under ultrasound radiation at 80 oC using ethanol as solvent in presence of few drops of acetic acid. Method B was a classical reflux method using ethanol as solvent in presence of few drops of acetic acid. Method A proved to be superior in terms of yields and reaction time. The thionation of 143a-h using lawesson`s reagent afforded 144a-f. The intermediates 1,2-disubstituted-2,3-dihydroquinazolin-4(1H)-ones 154a-l were afforded by Schiff base reaction of N-substituted anthranilamides with different aldehydes in glacial acetic acid. Compounds 155a-l were afforded through oxidation reaction of 154a-l using potassium permanganate in acetone. Fusion of thiourea with different substituted anthranilic acid through molecular cyclization afforded 2-thioxo-2,3-dihydroquinazolin-4(1H)-ones 165a-c. The product was reacted with benzyl bromide in DMF/ potassium carbonte to afford disubstituted 2-benzylthio quinazolin-4(3H)-ones 167a-c that was thionated using lawesson`s reagent to give disubstituted 2-benzylthio quinazoline-4(3H)-thiones 168a-c. 2. Molecular Docking Part: In this part, all the synthesized compounds were docked in the binding site of enzyme PDE7A1 using MOE 2007.09 program. The catalytic domain of enzyme PDE7A1 in complex with 3-(2,6-difluorophenyl)-2-methylthioquinazolin-4(3H)-one was obtained from the RCSB Protein Data Bank (PDB entry 3G3N). Twenty compounds 127b-d,h,I, 143b,c,d,g, 144a,c, 155b, d, e, g-i and 165a-c were capable of binding at the enzyme binding site in an inhibitory mode. They showed the two essential types of interactions; stacking against Phe416, and H-bond interaction against Gln413. Two compounds 127i and 143d showed high binding affinity of -11.90 and -11.28 Kcal/mol, respectively. The reference drug BRL50481, on the other hand, showed binding affinity of -11.17 Kcal/mol. 3. Biological Activity Part: In this part, twenty-eight of the synthesized compound were screened for their enzyme inhibitory activity against recombinant PDE7 enzyme. All the tested compounds showed high inhibitory activity at micro-molar levels. The IC50 of compounds 127c, 127f, 127i, 143d and 143e were 0.005, 0.007, 0.004, 0.006, 0.008 μM, respectively compared to the reference drug BRL50481 that showed IC50 of 0.07 μM. These five compounds 127c, 127f, 127i, 143d and 143e, were further evaluated against Jurkat, Clone E6-1 to assess their inhibitory activity. Compounds showed weak to moderate inhibitory activity. Compounds 127i and 143d showed IC50 of 67.5 and 40.1 μM, respectively indicating moderate inhibitory activity against PDE7 in the cell line screening. There was an agreement between the molecular docking results and the biological screening, where compounds 127i and 143d showed the highest binding affinity in the molecular docking study and highest inhibitory activity in both enzyme assays.